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PubMed1991

Oxygen-dependent erythropoietin production by the isolated perfused rat kidney.

In this study we have investigated the role of oxygen delivery and of classic second messengers on erythropoietin production by the isolated perfused rat kidney. We found that the rat kidney was capable of de novo synthesis of erythropoietin. The erythropoietin production rate was inversely related to the oxygen pressure in the perfusate and increased from 0.17 to 1.85 U erythropoietin h-1 g kidney-1 when arterial PO2 was lowered from 500 mmHg to 30 mmHg. Addition of forskolin (10 microM) and 8-bromo-cGMP (100 microM) to the perfusate elicited significant effects on the renal vascular resistance, but had no significant effect on erythropoietin production. Hypoxia-induced erythropoietin formation, however, was blocked by calmidazolium (1 microM) and W-7 (10 microM), two structurally different putative calmodulin antagonists. Calmidazolium and W-7 had no effect on other functional parameters of the isolated perfused rat kidney such as flow rate, glomerular filtration rate or sodium reabsorption. Our findings suggest that the oxygen-sensing mechanism that controls renal erythropoietin production is primarily located in the kidney itself. A calcium/calmodulin-dependent cellular reaction could be involved in the signal transduction process.

Animals↗
PubMed1993

The source of epifluorescence in isolated perfused heart loaded with fura 2-AM or indo 1-AM.

The purpose of this study is to clarify the kinds of cells that fluoresce in isolated perfused heart intracoronarily loaded with fura 2-AM or indo 1-AM. The hearts from hamsters perfused by the Langendorff method were loaded with fura 2-AM or indo 1-AM intracoronarily. The epicardium was excited by ultraviolet light at a wavelength of 340 or 380 nm (fura 2) or 360 nm (indo 1). Epifluorescent images from arrested hearts prepared with St Thomas' cardioplegic solution were observed through an inverted microscope and taken by a still camera. Endothelial cells and pericytes of the capillaries showed intense fluorescence. In the intercapillary spaces, a less intense but still apparent fluorescence emitted by myocytes could also be detected. On the other hand, fluorescence from smooth muscle cells and fibroblasts could not be identified. Therefore, epifluorescence in the isolated perfused heart loaded with fura 2-AM or indo 1-AM was mainly generated within endothelial cells, pericytes, and myocytes. To evaluate calcium fluorescence in isolated hearts quantitatively, the fluorescence of endothelial cells and pericytes of the capillaries must be taken into consideration.

Animals↗
PubMed1996

Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.

OBJECTIVE: The aim of this study was to investigate whether diabetes and hypertension cause additive effects in the responses to various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained from streptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats (SHR). METHODS: SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into a lateral tail vein at age 12 weeks. Eight weeks later the kidneys were isolated and perfused via the left renal artery with a physiological salt solution. Renal perfusion pressure was measured continuously. Concentration response curves were plotted for various vasoconstrictor and vasodilator agents. RESULTS: Both the diabetic and the hypertensive state were associated with an increased wet kidney weight. The contractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) and angiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of the sensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those from normoglycaemic WKY rats. The maximal contractile responses both to PhE and to Ang II were enhanced in kidneys from SHR compared with those in kidneys from their normotensive controls, whereas simultaneously occurring diabetes impaired this sensitization. After precontraction with 3 x 10(-6) mol/l PhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside) vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups of animals. CONCLUSION: In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, the isolated diabetic state did not influence the vasoconstriction caused by various agonists. However, the enhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetes mellitus. Endothelium-dependent and -independent vasorelaxation in this model was not affected neither by the hypertensive nor by the diabetic state.

Animals↗
PubMed1984

Transport activity modifies thick ascending limb damage in the isolated perfused kidney.

The thick ascending limb of Henle's loop ( TAL ) develops a specific and consistent structural lesion during perfusion of the isolated rat kidney that progresses from mitochondrial swelling at 15 min to complete cellular disruption at 90 min. Because it seemed possible that damage localized to this metabolically active portion of the nephron might be correlated with cellular transport, the histology of perfused kidneys was examined when transport activity in the TAL was varied. The fraction of TAL tubules showing severe damage (44 +/- 2% in kidneys perfused with glucose) was dramatically reduced by furosemide (7 +/- 2%; P less than 0.001). The lesion was eliminated by perfusion with ouabain or by preventing glomerular filtration. On the other hand, protection of TAL cells was not obtained with the proximal diuretic acetazolamide. These results suggest that the lesion of TAL cells that develops during perfusion of the isolated kidney is influenced by the work of cellular transport.

Acetazolamide↗
PubMed1984

Acute effects of nicotine on hemodynamic and metabolic parameters of isolated, perfused hearts of guinea pigs and rats.

Nicotine infused in concentrations greater than 10(-6) M exerted a dose-dependent negative inotropic effect on isolated, perfused hearts of guinea pigs (Langendorff and working heart preparations). This effect became manifest after an initial positive inotropic and positive chronotropic response had subsided. Furthermore, the stimulation of cardiac contractility by norepinephrine (concentration less than 10(-7) M) was attenuated by nicotine in the guinea pig heart, but not in isolated, perfused hearts of Sprague-Dawley rats. Nicotine inhibited the positive inotropic effect of catecholamines according to the order norepinephrine greater than epinephrine greater than isoproterenol. In no case did nicotine have a marked negative chronotropic action. Changes in coronary flow, oxygen consumption, and the release of lactate and adenosine were in keeping with the state of myocardial activity in the presence of nicotine. The drug did not significantly alter myocardial uptake or release of norepinephrine during expression of its negative inotropic action. Prazosin, phentolamine, cocaine, and hexamethonium suppressed both the nicotine-induced transient stimulatory response and the negative inotropic effect in norepinephrine-stimulated hearts. In the presence of theophylline and at high perfusate calcium levels (7.5 mEqu/l) the negative inotropic effect was alleviated. The cardiodepressive action of nicotine may possibly evolve from a weak blockade of beta 1-adrenoceptors. Direct modifications of myocardial Ca2+-transport could not be observed.

Animals↗
PubMed1996

Glomerular filtration and saturable absorption of iohexol in the rat isolated perfused kidney.

1. The renal handling of iohexol was examined in the rat isolated perfused kidney (IPK) over a perfusate concentration range of 5-20 micrograms ml-1. 2. At a concentration of 5 micrograms ml-1, a ratio of renal clearance over clearance by glomerular filtration (ClR/GF) of 0.63 +/- 0.06 could be determined. This ratio increased until 1.02 +/- 0.06 at 20 micrograms ml-1, indicating that a saturable mechanism is involved in the luminal disappearance of the drug. 3. Pretreatment of the kidneys with polylysine, probenecid or diatrizoate resulted in a significantly enhanced clearance of iohexol, probably due to inhibition of membrane binding. Renal clearance data were fitted to a kinetic model including filtration into the primary urine followed by saturable absorption at the luminal membrane. An absorption constant, KA, of 7.3 +/- 1.3 micrograms ml-1, and a maximum rate of absorption, VA,Max, of 1.4 +/- 0.1 micrograms min-1 were determined. 4. Iohexol accumulated in kidney tissue, reaching a concentration of 2 to 7.5 times the perfusate concentration. In freshly isolated proximal tubular cells and kidney cortex mitochondria, iohexol reduced the uncoupled respiratory rate at a concentration comparable to the highest tissue concentration found in the IPK. 5. In conclusion, iohexol is not only filtered by the kidney but also reabsorbed via a saturable mechanism, which results in tubular accumulation. Intracellularly sequestered iohexol may affect mitochondrial oxidative metabolism. Our results indicate that iohexol is not a true filtration marker.

Animals↗
PubMed1976

Evaluation of redox state of isolated perfused rat lung.

The metabolic responsiveness of lung tissue to inhibition of oxidative metabolism was determined by measurement of the redox state of the isolated perfused and ventilated rat lung. Changes in redox state were evaluated by fluorescence from the lung surface at wavelengths suitable for reduced pyridine nucleotides and by measurement of the ratios of redox couples in rapidly frozen lung tissue. Maximal change of redox state was observed during ventilation with carbon monoxide; surface fluorescence increased 6.6%, lactate/pyruvate increased 5.8 times, glycerol 3-P/dihydroxyacetone-P increased fourfold and glutamate/alpha-ketoglutarate doubled. KCN infusion resulted in similar changes. Hypoxia produced with N2 ventilation resulted in less than maximal changes in redox couple ratios until alveolar PO2 was reduced below 0.1 mmHg. Redox changes observed during infusion of 0.5 mM aminoxyacetic acid suggested that maintenance of cytoplasmic redox state depended on functioning of a malate-aspartate "shuttle." The isolated perfused lung appears suitable to study factors controlling pulmonary parenchymal oxidative metabolism. The results emphasize the need for ventilation with CO to establish intracellular anoxia.

Amobarbital↗
PubMed1991

Segmental vascular resistance in isolated perfused rat lungs. Influence of vasomotor tone and cyclooxygenase and lipoxygenase inhibition.

We have determined the profile of pressures in isolated perfused lungs of adult rats and investigated the influence of vasomotor tone and cyclooxygenase and lipoxygenase inhibition on total and segmental vascular resistance. We isolated and blood-perfused lungs of 30 rats (480 +/- 21 g). Group 1 (n = 7) was untreated, group 2 (n = 8) was paralyzed with papaverine, group 3 (n = 11) was treated with indomethacin, and group 4 (n = 4) was treated with indomethacin and U60257, a putative lipoxygenase inhibitor. Blood flow was adjusted initially to raise pulmonary artery pressure to approximately 15 cm H2O and then held constant. Airway and left atrial pressures were held constant at 7 and 8 cm H2O, respectively (zone 3 conditions). In all lungs, we measured pressures in subpleural 20-50-microns-diameter arterioles and venules using the micropuncture servonull technique. Thus, the pulmonary circulation was partitioned into three segments: arteries, microvessels, and veins. In group 1 lungs, arteries presented the largest fractional resistance to flow at 46% of total resistance, with microvessels and veins contributing 34% and 20%, respectively. In group 2 lungs that had no vasomotor tone, total vascular resistance was approximately 27% lower than in group 1 lungs, mainly due to a lower resistance in veins. In indomethacin-treated lungs (group 3) and indomethacin and U60257-treated lungs (group 4), total and segmental vascular resistance was not significantly different from untreated lungs (group 1). We conclude that in isolated perfused rat lungs, arteries are the predominant site of resistance to blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit.

We have previously shown that porcine endothelin (ET-1) releases endothelium-derived relaxing factor (EDRF) in the rat isolated perfused mesentery. Here we show that both ET-1 (1-100 pmol) and rat endothelin (ET-3, 1-300 pmol) release EDRF in this preparation and that ET-1 releases EDRF from the luminally perfused aorta of the rabbit. Furthermore, we confirm that, as a pressor agent, ET-1 is greater than 10 times more potent than ET-3. Vasodilatations in the rat isolated perfused mesentery in response to ET-1 and ET-3 were due to the release of EDRF since they were inhibited by removal of the endothelium, methylene blue (100 microM), or hemoglobin (30 microM). ET-3 was more selective than ET-1 as a vasodilator because ET-1 induced vasodilatations were limited and in the higher doses overwhelmed by concurrent vasoconstrictions. Release of EDRF from the rabbit aorta in response to ET-1 but not to other agonists (acetylcholine, substance P, or adenosine diphosphate) was potentiated by infusion of potassium chloride (3 mM). Bay K 8644 failed to release EDRF in either system or to constrict the nondepolarized rat mesentery. Thus, both ET-1 and ET-3 release EDRF by activation of receptors or channels that differ from dihydropyridine-sensitive calcium channels.

Animals↗
PubMed1983

Proton electrochemical potential of the inner mitochondrial membrane in isolated perfused rat hearts, as measured by exogenous probes.

The membrane potential (delta psi) and delta pH of the inner mitochondrial membrane were studied in isolated perfused rat hearts using exogenous labelled probes and tissue fractionation in non-aqueous media. The mitochondrial delta psi, measured by means of the subcellular distribution of [3H]triphenylmethylphosphonium (TPMP+), was 125 +/- 7 mV (negative inside) in hearts beating at 5 Hz and 150 +/- 3 mV (negative inside) in hearts beating at 1.5 Hz. The mitochondrial membrane delta pH, measured by means of the subcellular distribution of low concentrations of [1-14C]propionate, was 0.63 +/- 0.06 pH units (alkaline inside) in hearts beating at 5 Hz and 0.53 +/- 0.12 pH units (alkaline inside) in hearts beating at 1.5 Hz. The implication of proton and electron gradients in the regulation of cellular respiration is discussed. In combination with previous evidence on adenylate distribution in the isolated perfused rat heart, the results indicate that the mitochondrial electrogenic adenylate translocator is in near equilibrium with delta psi.

Adenylyl Cyclases↗
PubMed1993

Cadmium transport and toxicity in isolated perfused segments of the renal proximal tubule.

We measured the lumen-to-bath transport and assessed the toxicity of inorganic cadmium (Cd2+) in isolated, perfused segments of the rabbit renal proximal tubule. To determine the dose range for acute toxicity the segments (S1, S2, and S3) were perfused with cadmium chloride (CdCl2) and the vital dye, FD & C green. We observed the tubular epithelial cells under the light microscope for signs of cellular injury and necrosis. Cellular swelling, blebbing of the luminal membrane, and cellular vacuolization were indicators of cellular injury, and the uptake of dye was indicative of cellular necrosis. Visible cellular damage occurs within 45 min after exposure of renal proximal tubular cells to cadmium concentrations greater than 500 microM. To determine rates of transport and cellular uptake of cadmium, the segments were perfused with a mixture of 109CdCl2 and the volume marker, L-[3H]glucose. We added nonradioactive CdCl2 to vary the total cadmium concentration from 1.5 to 2000 microM. After perfusion, we treated the tubules with 3% trichloroacetic acid or with a buffer solution of reduced osmolality in an attempt to determine the fate of the cadmium reabsorbed from the lumen. The tubular transport of cadmium was measured as the rate of disappearance of cadmium from the lumen (JD, pmol min-1 mm-1) and as the rate of appearance of cadmium in the bath (JA, pmol min-1 mm-1). In transport experiments, increasing the concentration of cadmium in the lumen caused an increase in the leak of the volume marker from the lumen into the bath. Cadmium disappeared from the lumen much more rapidly than it appeared in the bath for all three tubular segments. We conclude that (i) ionic cadmium, at concentrations greater than 500 microM, is acutely toxic to cells of isolated, perfused renal proximal tubules, and this toxicity is greater in the S1 than in the S2 or S3 segments; (ii) it is avidly taken up at the luminal membrane in all three segments; uptake is greater in the S1 than in the S2 or S3 segments; (iii) less than 10% of the cadmium that disappears from the lumen is transported across the basolateral membrane into the bath; and (iv) appearance flux into the bath does not show saturation in any of the segments over the concentration range studied; disappearance flux from the lumen shows saturation in the S2 and S3 segments, but not in the S1 segment.

Animals↗
PubMed1985

The effect of acute liver damage on circulating ferritin levels in vivo and in the isolated perfused rat liver.

The effects of minimal acute liver injury on circulating ferritin levels have been examined in the rat both in vivo and in the isolated perfused liver. Liver damage produced by 6 mmol/kg of D-galactosamine (GalN) in vivo resulted in a marked rise in plasma ferritin levels 4 h after administration, 2 h before any significant increase in plasma aspartate transaminase. In the isolated perfused liver, damage produced by 5mM GalN introduced into the perfusate also produced an early increase in circulating ferritin before any evidence of release of intracellular enzymes, or alteration in liver histology as assessed by light microscopy was apparent. It is concluded that minimal acute liver damage results in a pronounced increase in circulating ferritin levels before other evidence of liver dysfunction. This is unlikely to be due solely to increased release from damaged cells but may rather result from an alteration in the mechanism responsible for ferritin homeostasis.

Animals↗
PubMed1981

Alternation by histamine receptor agonists of the release of adrenergic transmitter in the isolated perfused rabbit kidney.

The effects of histamine and synthetic H1 and H2-receptor agonists on the release of neurotransmitter were studied in the isolated perfused rabbit kidney. The increase in perfusion pressure and the contraction of the venous outflow-superfused rabbit aortic strip were taken as the parameters for the evaluation of the elaboration of neuromediator from the kidney du to periarterial stimulation. Histamine and te specific histamine H1-receptor agonist, 2-(2-thiazolyl) ethylamine, caused a significant increase but the specific H2-receptor agonists, dimaprit and impromidine, produced a significant decrease in the response due to periarterial stimulation without altering that of exogenously applied noradrenaline. Prior addition of mepyramine to the medium prevented effect of 2-(2-thiazolyl) ethylamine but caused a high significant decrease in the response produced by histamine when compared with the control values. Prior addition of metiamide to the medium, however, prevented the inhibitory effect of dimaprit and impromidine but potentiated the effect of histamine. From these results it was concluded that histamine has a presynaptic H1-mediated facilitatory and H2-mediated inhibitory effects on the release of neurotransmitter from adrenergic neurons in the isolated perfused rabbit kidney.

Animals↗
PubMedDate not supplied

Endothelin-3 modulates glomerular filtration rate in the isolated perfused rat kidney.

The present study has been performed to evaluate hemodynamic and tubular effects of various endothelin-3 (ET-3) concentrations on the isolated perfused rat kidney. Using this experimental system we observed a profound reduction of renal perfusate flow at all ET-3 concentrations tested (50, 250 and 500 pmol/l), suggesting that the vasoconstrictive potency of ET-3 in the kidney is comparable to that described for endothelin-1 (ET-1). The effects on glomerular filtration rate (GFR) differed depending on the ET-3 dose applied. While 250 pmol/l ET-3 increased GFR by 30%, 500 pmol/l ET-3 markedly reduced GFR. 50 pmol/l ET-3 did not alter GFR although renal vascular resistance significantly increased. Infusion of 1 mumol/l N-nitro-L-arginine, a specific and potent inhibitor of nitric oxide synthesis in endothelial cells, abolished the GFR elevation induced by 250 pmol/l ET-3. In parallel with the changes of GFR we observed an increase in sodium reabsorption at 250 pmol/l and a decrease of this parameter at 500 pmol/l ET-3. Moreover, an ET-3 concentration (500 pmol/l), which induced a dramatic fall in tubular sodium load, led to an increase of fractional sodium excretion and to a decrease of renal oxygen consumption. We conclude that ET-3 is a potent vasoconstrictor in the isolated perfused rat kidney. Furthermore, it modulates GFR in a differentiated mode, depending on the concentration used. The GFR increase at 250 pmol/l ET-3 seems to be mediated by endothelium-derived nitric oxide. In addition to its glomerular action, ET-3 might also affect tubular sodium transport.

Animals↗
PubMed1996

Nitric oxide regulates insulin secretion in the isolated perfused human pancreas via a cholinergic mechanism.

BACKGROUND: The purpose of this study was to determine whether nitric oxide regulates insulin secretion in the isolated perfused human pancreas. METHODS: Single-pass perfusion was performed in four pancreata with a modified Krebs medium. Sequential 10-minute infusions (separated by 10-minute basal periods) of (1) 25 nmol/L acetylcholine, (2) 2.5 mumol/L acetylcholine, and (3) 16.7 mmol/L glucose were initially infused. Then 0.1 mumol/L of NG-monomethyl-L-arginine (NMMA) was infused during a period of 10 minutes, and steps (1) through (3) were repeated. The change in insulin secretion from basal levels during each stimulation was calculated and compared with that seen after NMMA infusion. RESULTS: Infusion of 25 nmol/L and 2.5 mumol/L acetylcholine resulted in a significant stimulation of insulin secretion before NMMA infusion (p < 0.05) and after NMMA infusion for acetylcholine at 25 nmol/L (p < 0.05). There was a significant decrease in acetylcholine-induced insulin secretion after NMMA infusion for acetylcholine at 25 nmol/L and 2.5 mumol/L compared with before NMMA infusion (p < 0.05). Infusion of 16.7 mmol/L glucose significantly stimulated insulin secretion before and after NMMA infusion, but there was no significant difference seen with insulin secretion before and after NMMA infusion. Insulin secretion was significantly inhibited during NMMA infusion (p < 0.05). CONCLUSIONS: These data show that infusion of the nitric oxide synthase inhibitor NMMA suppressed cholinergic-stimulated insulin secretion but did not affect glucose-stimulated insulin secretion. We conclude that nitric oxide regulates insulin secretion in the isolated perfused human pancreas.

Acetylcholine↗
PubMed1993

The role of nitric oxide derived from L-arginine in the control of steroidogenesis, and perfusion medium flow rate in the isolated perfused rat adrenal gland.

The present studies were designed to investigate the role of nitric oxide (NO) in the regulation of adrenocortical function, using the intact rat adrenal gland in situ, perfused with medium (Hank's balanced salt solution) containing a range of concentrations of L-arginine, the substrate for NO production. In addition, the effects of NG-nitro-L-arginine methylester (L-NAME), an inhibitor of NO production, were investigated. Results showed that L-arginine caused a dose-dependent increase in the flow rate of the perfusion medium through the adrenal gland. This effect was specific, as neither D-arginine nor L-lysine had an effect. The presence of L-NAME (5 mmol/l) in perfusion medium containing L-arginine caused a decrease in flow rate to levels in the absence of L-arginine. In the presence of concentrations of L-arginine up to 500 mumol/l, corticosterone secretion rates were also stimulated in a dose-dependent manner. Further studies, investigating the effect of L-arginine on the response to ACTH(1-24) stimulation, found that the percentage increase in flow rate, aldosterone secretion and corticosterone secretion caused by ACTH were not significantly different using media containing 230 mumol L-arginine/l or in the absence of L-arginine. These results suggest a role for NO derived from L-arginine in the regulation of basal levels of adrenal vascular tone in the rat isolated adrenal gland preparation. They do not suggest an obligatory role for NO in either the vascular or steroidogenic response to ACTH stimulation.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Effect of hyperthermia on cisplatin (CDDP) disposition to isolated perfused skin.

Hyperthermia has previously been postulated to enhance tissue uptake of systemically administered chemotherapeutic drugs. Normothermic (36.2 degrees C) and hyperthermic (42.1 degrees C) isolated perfused porcine skin flaps (IPPSF) were infused with cisplatin (CDDP) to assess any influence of heat on drug disposition to skin. A three-compartment physiologically relevant model was employed to interpret kinetically the measured arterial and venous flux profiles. Additionally, non-parametric methods were applied to these data in an effort to confirm the propriety of the model. Results of both approaches suggest that heat does not increase tissue uptake of CDDP after infusion in isolated perfused skin, although it does increase the mobility of CDDP as evidenced by shorter transit times through the IPPSF. These findings are similar to those seen in skin in vivo, but do not predict the enhanced in vivo uptake seen with hyperthermia in more highly perfused tissues.

Animals↗
PubMed1991

Clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg.

The clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg were studied in five patients exhibiting solitary, localized malignant melanoma. Mitoxantrone was given as four 1-min infusions at 15-min intervals into the arterial line of the perfusion system at a total dose of up to 14 mg/m2. The mean half-lives for mitoxantrone in the blood circulation of the leg were: t1/2 alpha (distribution phase), 25.5 s, and t1/2 beta (elimination phase), 14.9 min. The mean volume of distribution at steady state in the leg was 25.6 1. In the arterial part of the perfusion, the mean AUC was 155.9 mg min l-1, and that in the corresponding venous part was 91.6 mg min l-1. Leakage of the drug from the leg into the systemic circulation amounted to 1.2% of the total delivered dose; 91% of the delivered dose remained in the leg after the perfusion had been completed. The mean elimination half-life of mitoxantrone in the systemic circulation was 123 min and the corresponding AUC for systemic concentrations was 8.59 mg min l-1. The present data revealed a high uptake of mitoxantrone into the leg and low systemic drug concentrations due to minor leakage, suggesting that mitoxantrone might be a good candidate for use in isolated, hyperthermic limb perfusion.

Adult↗